It has been established that many human tumours contain a significant proportion of hypoxic cells (Kennedy et al., Int. J. Radiat. Oncol. Biol. Phys., 1997, 37, 897-905; Vaupel et al., Semin. Oncol., 2001, 28, 25-35). The presence of hypoxic cells arises because of chaotic growth and an inefficient microvasculature system within the tumour, so that tumours often exhibit large intercapillary distances and variable blood flow. Reduction of oxygen tension in tumours leads to radioresistance. Up to a three-fold increase in radiation dose may be required to kill anoxic tumour cells. A link has been identified between the presence of tumour hypoxia and failure of local control by radiation therapy (Nordsmark et al., Radiother. Oncol., 1996, 41, 31-39; Brizel et al., Radiother. Oncol., 1999, 53, 113-117). This phenomenon of tumour hypoxia has been exploited in the development of a class of anticancer agents termed ‘hypoxia-activated prodrugs’ which are also sometimes referred to as ‘bioreductive drugs’ although the latter term also encompasses prodrugs activated by reduction under oxic conditions (Brown et al., Semin. Radiat. Oncol., 1966, 6, 22-36; Denny et al., Br. J. Cancer, 1996, 74 (Suppl XXVII) 32-38; Stratford & Workman, Anti-Cancer Drug Des., 1998, 13, 519-528).
Various nitro(hetero)aromatic compounds have been reported as hypoxia-activated prodrugs. These include                the nitroimidazole (i), which is proposed to undergo fragmentation following nitro group reduction by endogenous cellular nitroreductase enzymes (McClelland et al., Biochem. Pharmacol., 1984, 33, 303-309),        the dinitrobenzamide mustard (ii) and analogues, where similar reduction of the nitro group activates the mustard (Palmer et al., J. Med. Chem. 1996, 39, 2518; Helsby et al., Chem. Res. Toxicol., 2003, 16, 469-478; Denny et al., NZ Provisional Patent Application 529249), and        the nitrobenzindoline (iii) and analogues have been reported as potential bioreductive drugs activated by the E. coli NR enzyme (Denny et al., PCT Int. Appl. WO 98/11101 A2, 1998; Atwell et al., J. Org. Chem. 1998, 63, 9414-9420; Atwell et al., Bioorg. Med. Chem. Lett. 1997, 7, 1493-1496.)        

It is an object of the present invention to provide a specific class of nitro-1,2-dihydro-3H-benzo[e]indoles, and their corresponding phosphates, as bioreductive prodrugs for use in cancer therapy or to at least provide the public with a useful alternative.